Isothiocyanobenzazoles

ABSTRACT

1. A COMPOUND OF THE GENERAL FORMULA   1,2-(-X-C(-(Y)N-R1)=N-),R2,(S=C=N-)-BENZENE   WHEREIN THE SCN- GROUP IS IN THE 4-, 5-, 6- OR 7-POSITION, R1 REPRESENTS HYDROGEN, A STRAIGHT-CHAIN OR BRANCHED ALKYL OR ALKENYL RADICAL HAVING AT MOST 17 CARBON ATOMS, AN ALKYL OR ALKENYL RADICAL HAVING A TOTAL OF AT MOST 6 CARBON ATOMS AND SUBSTITUTED BY HALOGEN, -CN, -OH, C1-C5 ALKOXY, C1-C5 ALKYLTHIO OR DI(C1-C5)ALKYLAMINO, AN OPTIONALLY C1-C5 ALKYL-SUBSTITUTED MONO-, BI- OR TRICYCLIC CYCLOALKYL OR CYCLOALKENYL RADICAL HAVING 3 TO 10 CARBON ATOMS IN THE RING STRUCTURE, WHICH CAN ALSO BE BOUND BY WAY OF A CH2- GROUP TO THE SUBSTITUENT Y OR TO THE 2-POSITION OF THE HETEROCYCLC, R2 REPRESENTS HYDROGEN HALOGEN OR AN ALKYL OR ALKOXY RADICAL HAVING AT MOST 4 CARBON ATOMS, X REPRESENTS OXYGEN, SULPHUR OR   &gt;N-R3   R3 REPRESENTS HYDROGEN, AN ALKYL OR ALKENYL RAICAL HAVING AT MOST 5 CARBON ATOMS, A PHENYL OR BENZYL RADICAL, A DIMETHYLAMINO- OR DIETHYLAMINO-ALKYL RADICAL HAVING 2-5 CARBON ATOMS IN THE ALKYL CHAIN, AN ALKOXYCARBONYL RADICAL HAVING 2-5 CARBON ATOMS, ACETYL, PROPIONYL, TRICHLOROACETYL, BENZOYL, OR A C4-C7 SACCHARIDE GROUP, Y REPRESENTS OXYGEN, SLPHUR, -SO-, -NR4, -, -SO2-, OR N I THE NUMBER 0 OR 1, R4 REPRESENTS HYDROGEN, AN ALKYL OR ALKENYL RADICAL HAVING AT MOST 5 CARBON ATOMS, OR TOGETHER WITH THE NATOM AND THE SUBSTITUENT R1 A SATURATED OR UNSATURATED HETEROCYCLE HAVING 4 TO 6 CARBON AOMS WHICH MAY ALSO CONTAIN A FURTHER HETERO ATOM O OTOMS WHICH LEC ED FROM THE GROUP CONSISTING OF PYRROLIDINE, PIPERIDINE, 2-METHYLPIPERIDINDE, 4-METHYLPIPERIDINE, PIPERAZINE, N&#39;&#39;-METHYL, N&#39;&#39;,N&#39;&#39;-DI-METHYL AND N&#39;&#39;-ETHYL PIPERAZINE, MORPHOLINE, ISOMORPHOLINE, THIOMORPHOLINE AND HEXAMETHYLENEIMINE, OR THE GROUP   &gt;N-R5   AND R5 STANDS FOR HYDROGEN, METHYL OR ETHYL AND THEIR ACID ADDITION SALTS NON-TOXIC FOR WARM-BLODDED ANIMALS.

U.S. Cl. 260-306.6 R Claims ABSTRACT OF THE DISCLOSURE =New isothiocyanobenzazoles of the formula S ON n'Rl wherein R is hydrogen, optionally substituted alkyl, alkenyl,

cycloalkyl or cycloalkenyl,

R is hydrogen, halogen, alkyl, alkoxy or alkanoyl,

X is oxygen, sulfur or 11IR3| R is hydrogen, alkyl, alkenyl, phenyl or benzyl, dialkylaminoalkyl, alkoxycarbonyl, alkauoyl or polyhydroxyl, Y is oxygen, sulfur,

-SO, -SOz or -1 IR4, n is or 1, and R is hydrogen, alkyl or alkenyl or together with the nitrogen atom and R, a saturated or unsaturated heterocyclic which may contain one further hetero atom having anthelmintic and microbicidal activity.

The present invention relates to isothiocyanobenzazoles, to processes for the production of these new compounds, as well as to anthelmintic and microbicidal agents containing these compounds as active components.

Among the endoparasites occurring in the case of warmblooded animals, the helminthes, in particular, cause considerable damage. For example, animals infested by worms sufier not only to the extent of retarded growth but, in some cases, to the extent of injury so severe that the animals die as a result. It is therefore of great importance that agents be developed which are suitable for the control of helminthes and of their development stages, as well as for the prevention of infestation by these parasites. By the term helminthes in the present description are meant nematodes, cestodes and trematodes, that is, worms of the gastrointestinal tract, of the liver and of other organs. A number of substances having anthelmintic action have indeed become known; however, these are frequently not entirely satisfactory for the given application: it may be that they have an insufiicient action in compatible dosages, produce in therapeutically effective dosage levels undesired secondary etfects, or have too narrow a range of action. Thus, for example, racemic 2,3,5,6-tetrahydro-6- phenyl-imidazo(2,1-)thiazole, known from the Dutch Pat. No. 6505806, is effective only against nematodes, not, however, against trematodes and cestodes.

The new isothiocyanobenzazoles corresponds to formula I ted States Patent Office 3,849,431 Patented Nov. 19, 1974 wherein the SCN group is in the 4-, 5-, 6- or 7-position, and preferably in the 5- or 6-position, and wherein R represents hydrogen, a straight-chain or branched alkyl or alkenyl radical having 1 to 17, preferably 1 to 5 carbon atoms, a lower alkyl or alkenyl radical having a total of at most 6 carbon atoms and substituted by halogen, CN, -OH, alkoxy, acyl, alkylthio or dialkylamino, an optionally lower-alkyl-substituted, mono-, bior tricyclic cycloalkyl or cycloalkenyl radical having 3 to 10 carbon atoms in the ring structure, which can also be bound by way of a CH;; group to the substituent Y or to the heterocycle,

R represents hydrogen, halogen or an alkyl, alkoxy or acyl radical having at most 4 carbon atoms,

X represents oxygen, sulphur or R stands for hydrogen, an alkyl or alkenyl radical having at most 5 carbon atoms, a phenyl or benzyl radical, a dimethylaminoor diethylaminoalkyl radical having 2-5 carbon atoms in the alkyl chain, an alkoxycarbonyl' radical having 2-5 carbon atoms, an aliphatic acyl radical having 2-5 carbon atoms, or for a polyhydroxyalkyl radical (saccharide),

Y represents oxygen sulphur,

n is the number 0 or 1,

R represents hydrogen, an alkyl or alkenyl radical having at most 5 carbon atoms, or together with the N-atom and the substituent R, a saturated or unsaturated heterocycle having 4 to 6 carbon atoms which may also contain a further hereto atom O or S or the group 'l IR and R stands for hydrogen, methyl or ethyl,

and include the acid addition salts non-toxic for warmblooded animals.

The compounds of formula 1 constitute therefore,

where X=-O, benzoxazole derivatives (Ia), where X=S, benzothiazole derivatives (lb), or where X=NR benzimidazole derivatives (Ic).

The benzoxazole derivatives Ia (X=0) are able, if n =0, to convert in a reversible reaction, with the aid of strong mineral acids, into N-acylaminophenols II according to the following diagram:

R2 0 H2O R2 [H+] 0H s CN R s CN A NH-OO-R| N =H20 Ia II Examples of straight-chain or branched alkenyl radicals are as follows: n-propenyl, a-methylvinyl, 9-decenyl and 8-heptadecenyl.

The meaning of cycloalkyl or cycloalkenyl radicals includes also ring structures which can be substituted by methyl, ethyl, n-propyl or isopropyl. The following ex amples may be given: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 3,4-dimethylcyclobutyl, 2,3-dimethylcyclopropyl, 4-methylcyclohexyl, 4-isopropylcyclohexyl, 3,5-bis-(ethyl)cyclohexyl, norbornyl, norbornylmethyl, adamantyl and adamantylmethyl.

The term halogen covers fluorine, chlorine and bromine.

By polyhydroxyalkyl radicals are meant saccharide groups, particularly C -C saccharides, such as sorbose, glucose, mannose and ribose.

Saturated or unsaturated heterocycles formed from the substituents R and R together with the N-atom bound to them are, e.g. pyrrolidine, piperidine, 2-methylpiperidine, 4-methylpiperidine, piperazine, N'-methyland N- ethyl-piperazine, morpholine, isomorpholine, thiomorpholine and hexamethyleneimine.

Suitable salts of isothiocyanobenzazoles non-toxic to warm-blooded animals are addition compounds with inorganic or organic acids, preferably fairly strong acids; examples of such acids are as follows: hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid, acetic acid, adipic acid, maleic acid, tartaric acid, lactic acid, citric acid, glutamic acid, aconitic acid, sulphamic acid, methanesulphonic acid and p-toluenesulphonic acid.

The compounds of formula I are highly effective against harmful bacteria and fungi, and against helminthes in all stages of development. The invention relates also to the application of compounds embraced by formula I as anthelmintics and antimicrobics.

Three important subgroups of compounds are those of formula I (benzoxazoles, benzothiazoles and benzimidazoles) and their addition salts wherein X represents oxygen, sulphur, or the group N(R defined for formula I, the SCN group is in the 5- or 6-position, n=0, and R, represents a straight or branched alkyl radical having 1 to 8 carbon atoms, a propenyl, S-heptadecenyl, heptadecyl or pentadecyl radical, or the cyclopropyl, cyclopropylmethyl, cyclobutyl, cyclopentyl or cyclohexyl radical, or wherein n=1, and YR denotes a(n) hydroxyl, methoxy, ethoxy, n-propoxy, isopropoxy, mercapto, methylmercapto, ethylmercapto, n-propylmercapto, isopropylmercapto, n-butylmercapto, methylsulphonyl or ethylsulphony], or a monoor dialkylamino radical having at most 6 carbon atoms, and R represents hydrogen, a chlorine or bromine atom, a methyl, methoxy or acetyl group.

The following compounds have proved particularly good active substances:

2- [n-amyl] -6-isothiocyanobenzothiazole, 2-isopropyl-6-isothiocyanobenzothiazole, 2-methyl-6-isothiocyanobenzothiazole, Z-ethyl-6-isothiocyanobenzothiazole,

2- [n-propyl] -6-isothiocyanobenzothiazole, 2- [n-amyl] -5-isothiocyanobenzothiazole,

2- [n-propyl] -5-isothiocyanobenzothiazole, 2-isopropyl-S-isothiocyanobenzothiazole, 2-ethyl-5-isothiocyanobenzothiazole, Z-[n-amyl] -6-isothiocyanobenzoxazole, 2-isopropyl-6-isothiocyanobenzoxazole, Z-ethyl-6-isothiocyanobenzoxazole, 2-tert.butyl-6-isothiocyanobenzothiothiazole, Z-cyclopropyl-6-isothiocyanobenzothiazole, 2- [n-amyl] -5-isothiocyanobenzoxazole, 2-isopropyl-5-isothiocyanobenzoxazole, Z-ethyl-S-isothiocyanobenzoxazole, 2-n-octyl-5-isothiocyanobenzoxazole, 2-ethoxy-6-isothiocyanobenzoxazole, Z-mercapto-6-isothiocyanobenzoxazole, Z-methylthio-S-isothiocyanobenzoxazole, 2-isopropylthio-S-isothiocyanobenzoxazole, 2-n-butylthio-6-isothiocyanobenzoxazole,

2-methylthio-6-isothiocyanobenzoxazole, Z-methoxy-6-isothiocyanobenzothiazole, 2-hydroxy-6-isothiocyanobenzothiazole, 2-isopropoxy-6-isothiocyanobenzothiazole, Z-methylthio-6-isothiocyanobenzothiazole, Z-ethylthio-6-isothiocyanobenzothiazole, Z-methylsulphonyl-6-isothiocyanobenzothiazole, 2-mercapto-6-isothiocyanobenzothiazole, 2-n-propylthio-5-( 6 isothiocyanobenzimidazole, 5 (6) -chloro-6(5 isothiocyanol-methoxycarbonyl-Z-npropylbenzimidazole, 5 (6) -isothiocyano-1-ethyl-2-methylbenzimidazole.

The new active substances of formula I according to the invention are suitable for the control of parasitic nematodes of the orders:

Dracunculoidia,

Ascaroidea (e.g. Ascaridia galli), Trichenelloidea,

Strongyloidea, Trichostrongyloidea, Metastrongyloidea,

or for the control of cestodes of the families:

Dilepididae (e.g. Hymenolepis nana), Taeniidae, Diphyllobotridae,

or for the control of trematodes of the families:

Dicrocoelidae, Fasciolidae (e.g. Fasciola hepatica), Schistosamatidae (e.g. Schistosoma bovis),

in the case of domestic and useful animals, such as cattle, sheep, goats, horses, pigs, cats, dogs, as well as poultry. The new active substances can be administered in single doses to the animals, or in repeated doses, the single doses preferably being, depending on the species of animal, between 25 and 1000 mg. per kilogram of body weight. A better effect can be obtained in some cases by a protracted administration of the active substances, or smaller total doses may sufiice to obtain the desired effect. The active substances or mixtures containing them can also be added to the feed or to the drinking water. The finished feed contains the substances of formula I preferably in a concentration of ca. 0.05 to 1.0 percent by weight.

The new active substances can be administered as agents orally or abomasally to the animals, the said agents being, for example, in the form of solutions, emulsions, suspensions (drenches), powders, tablets, boluses and capsules. The usual solid carriers are used to produce the above-mentioned preparations, such as, for example, kaolin, talcum, bentonite, sodium chloride, calcium phosphate, carbohydrates, cellulose powder, cottonseed meal, carbowaxes, and gelatin, or liquids such as water, optionally with the addition of surface-active substances such as ionic or non-ionic dispersing agents, as well as oils, and other solvents and diluents harmless to the animal organism. If the anthelmintic agents are in the form of feed concentrates, then the carriers used are, for example, production feed, fodder grain or protein concentrates. Such feed concentrates or agents can contain, in addition to the active substances, also additives, vitamins, antibiotics, chemotherapeutical agents, or other pesticides, chiefly bac teriostatics, fungistatics, coccidiostatics, also hormone preparations, substances having anabolic activity, or other substances promoting growth, affecting the quality of the meat of slaughter cattle, or in some other way beneficial for the organism.

Principally as nematocides:

Absonal Alcopar Anthelcide Ascaridole Badminth II Bephenium Bradosol Cambendazol Chlorophos Chlorthion Coumaphos Cyanin Destomycin Diethylcarbamazine Dichlorophene, DDVP 1,4-di-(D-glucosyl)-piperazine Dithiazonine Dow ET/ 70 Dowco 132 Dymanthine HCl Egressin Gainex Hexachlorophene Hexylresorcinol Ionit Levamisol Mebendazol Mepacrine Methylene violet l-methyl-1-tridecylpiperazinium-4-carboxylic acid ethyl ester Methyridine Monopar Narlene Neguvon Nematodin Nemural Nidanthel Parabendazol Parvex Phenothiazine Piperazine Polymethylene-piperazine Promethazine Pyrantel Pyrathiazine Pyryinium-embonate Rametin Ronnel Santonin Shell 1808 Stilbaziurn Tetramisole Thenium Thiabendazole Thymolan Triclofenol Treclofenol-piperazine Vermella Principally as trematocides:

Acedist Bilevon M Bilevon R Bithionol Disophenol Freon 112 Hetol Hetolin Hexachloroethane Hexachlorophene Hilomid Niclofolan Nitroxynil Ranide Tremerad Tribromsalan (Tremasept II) Zanil Brotianid Principally as cestocides:

Acranil Arecoline Atebrin Bithionol Bithionol oxide Bunamidine Cestodin Cambendazol Dibutyltin dilaurate Dichlorophen Dioctyltin dichloride Dioctyl tin laurate Doda Filixic acid Hexachlorophene Nidanthel Terenol Yomesan For combination with the active substances according to the invention, it is also possible to use preparations containing several active substances, e.g.:

Eldon:

Piperazine-hexahydro+copper metaarsenite Equizol A:

Thiabendazole-i-piperazine phosphate Nilzan:

Tetramisole+Zanil Nitroarene:

Yomesan+dichlorophene Parvec plus:

Phenothiazine+piperazine-CS -comp1ex Phenovis 2:

Phenylbenzimidazole+phenothiazine sulphate+sodium Microbicidal agents according to the invention are produced in a manner known per se by the intimate mixing and grinding of active substances of the general formula I with suitable carriers, optionally with the addition of dispersing agents or solvents which are inert to the active substances. The active substances can be obtained and used in the forms 'described below, the given information applying in some cases also to the production of anthelmintic agents:

solid preparations: dusts, scattering agents, granulates (coated granulates, impregnated granulates and homogeneous granulates);

water-dispersible concentrates of the active substance:

wettable powders, pastes, emulsions; liquid preparations: solutions.

The particle size of the carriers is for dusts advantageously up to about 0.1 mm.; for scattering agents from about 0.075 mm. to 0.2 mm.; and for granulates 0.2 mm.

or coarser.

The concentrations of active substance in the solid preparation forms are from 0.5 to 80%.

To these mixtures may also be added additives stabilising the active substance, and/or non-ionic, anion-active, and cation-active substances, which, for example, improve the adhesiveness of the active substances (adhesives and agglutinants), and/ or ensure a better wettability (wetting agents) and dispersibility (dispersing agents). Suitable adhesives are, for example, the following: olein/lime mixture, cellulose derivatives (methyl cellulose), hydroxyethylene glycol ethers of monoalkyl and dialkyl phenols having to ethylene oxide radicals per molecule and 8 to 9 carbon atoms in the alkyl radical, ligninsulphonic acids, their alkali metal and alkaline-earth metal salts, polyethylene glycol ethers (carbowaxes), fatty alcohol polyethylene glycol ethers having 5 to ethylene oxide radicals per molecule and 8 to 18 carbon atoms in the fatty alcohol moiety, condensation products of ethylene oxide, propylene oxide, polyvinyl pyrrolidones, polyvinyl alcohols, condensation products of urea and formaldehyde, as well as latex products.

Water-dispersible concentrates of active substance, i.e., wettable powders, pastes and emulsion concentrates, are agents which can be diluted with water to obtain any desired concentration. They consist of active substance, carrier, optionally additives which stabilise the active substance, surface-active substances, and anti-foam agents and, optionally, solvents. The concentration of active substance in these agents is 5 to 80%.

The wettable powders and the pastes are obtained by the mixing and grinding of the active substances with dispersing agents and pulverulent carriers, in suitable devices, until homogeneity is attained. Suitable carriers are, e.g. those previously mentioned in the case of solid preparations. It is advantageous in some cases to use mixtures of different carriers. As dispersing agents it is possible to use, e.g.: condensation products of sulphonated naphthalene and sulphonated naphthalene derivatives with formaldehyde, condensation products of naphthalene or of naphthalenesulphonic acids with phenol and formaldehyde, as well as alkali, ammonium and alkaline-earth metal salts of ligninsulphonic acid, also alkylaryl sulphonates, alkali metal salts and alkaline-earth metal salts of dibutyl naphthalenesulphonic acid, fatty alcohol sulphates such as salts of sulphated hexadecanols, heptadecanols, octadecanols, and salts of sulphated fatty alcohol glycol ether, the sodium salt of oleyl ethionate, the sodium salt of oleyl methyl tauride, ditertiary acetylene glycols, dialkyl dilauryl ammonium chloride, and fatty acid alkalimetal and alkaline-earth metal salts.

Suitable anti-foam agents are, for example silicones.

The active substances are so mixed, ground, sieved and strained with the above-mentioned additives that the solid constituent in the case of wettable powders has a particle size not exceeding 0.02 to 0.04 mm., and in the case of pastes not exceeding 0.03 mm. Dispersing agents such as those mentioned in the preceding paragraphs, organic solvents and water are used in the preparation of emulsion concentrates and pastes. Suitable solvents are, e.g. the following: alcohols, benzene, xylenes, toluene, dimethylsulphoxide, and mineral oil fractions boiling in the range of 120 to 350 C. The solvents must be practically odourless, non-phytotoxic, inert to the active substances, and not readily inflammable.

Furthermore, the agents according to the invention can be used in the form of solutions. For this purpose the active substance (or several active substances) of the general formula I is (or are) dissolved in suitable organic solvents, mixtures of solvents, or water. As organic solvents it is possible to use aliphatic and aromatic hydrocarbons, their chlorinated derivatives, alkylnaphthalenes,

Til

mineral oils on their own or in admixture with each other. The solutions should contain the active substances is a concentration of from 1 to 20% Other biocidal active substances, such as pesticides, may be added to the described agents according to the inven tion. For the widening of their sphere of action, the new agents may also contain, in addition to the stated compounds of formula I, e.g. fungicides, bactericides, fungistatics, bacteriostatics or nematocides, or other active substances.

Isothiocyanobenzazoles of formula I can be produced according to the invention by a process in which the basic aminobenzazoles of formula III R2 X 11mg Y ..R1

N (III) are (a) reacted with a thiocarbonic acid derivative of the formula Hal- TIE-Y S wherein Hal represents chlorine or bromine, and Y represents chlorine, bromine or a dialkylamino group; or

(b) reacted with a sulphide of the formula Alk Alk II s Alk wherein Alk denotes a lower alkyl radical having at most four carbon atoms; or

(c) reacted with pentathio-dipercarbonic acid-bis(trihalogenalkyl)-esters; or

(d) reacted with phosgene and phosphorus pentasulphide in a solvent or diluent inert to the reactants; or

(e) converted with benzoylisothiocyanate into the corresponding thiourea, and this thermally decomposed in the presence of a solvent inert to the reactants, preferably in an aromatic hydrocarbon or halogenated hydrocarbon, or in the presence of acids or acid anhydrides; or

(f) converted with carbon disulphide in the presence of an inorganic base, or of an amine, into the corresponding dithiocarbamic acid salts, and these then dehydrosulphated; or

(g) reacted with carbon disulphide in the presence of carbodiimides and of a tertiary amine; or

(h) reacted with ammonium rhodanide in the presence of gaseous hydrogen chloride.

The processes are performed in solvents or diluents which are inert to the reactants.

The following, for example, can be used in the process according to the invention: aliphatic and aromatic hydrocarbons, aliphatic and aromatic halogenated hydrocarbons, ethers and ethereal compounds such as dioxane or tetrahydrofuran, ketones, amides such as dimethylformamide, etc., water, or mixtures of such solvents with water.

In the preparation of isothiocyano compounds of formula I by the methods given under (a)(h), temperatures of between -20 and C. are maintained, preferably of between 10 and +30 C., and with application of a dialkylthiocarbamoyl halide such as diethylthiocarbamoyl chloride, or in the case of thermal decomposition according to method (e), higher temperatures of between 40 and 200 C. are used.

The formation of the isothiocyano group involves known methods: reactions of amines with thiophosgene (a) are described in Houben-Weyl, 4th edition, vol. 9, p. 876 (1955), the use of acid-binding agents by O. E. Schultz in Arch. Pharm., 295, 146-151 (1962); the reaction of amines with N,N-diethylthiocarban1oy1 chloride (a) has been described in Journal Org. Chem., 30, 2465 (1965), that with bis-thiocarbamoyl sulphides (b) by F. H. Marquardt in Helv. Chim. Acta, 49, 1716 (1966), and that with pentathiodipercarbonic acid-bis-(trihalogenoalky1)-ester (c) by R. Gottfried in Angew. Chem, 78, (1966), and that with phosgene and phosphorus pentasulphide according to Houben-Weyl, 4th edition, vol. 9, p. 867 if.

The preferred solvents for the reactions given under (d) and (e) are odichlorobenzene and chlorobenzene; other dichlorobenzenes, toluene, xylenes, cumol, etc. are however also suitable. The thermal decomposition of thioureas (e) is performed in the manner described by J. N. Baxter et. al. in J. Chem. Soc. (1956), p. 659 if. The thioureas are produced according to Org. Syntheses III, 735 (1955). The inorganic bases used in the production of dithiocarbamic acid salts (f) are, e.g the hydroxides, oxides and carbonates of alkali and alkaline-earth metals, as well as ammonium hydroxide; and the amines used are, e.g. trialkylamines, pyridine bases or ammonia (cp. C.A., 70, 3389q (1969)). Dehydrosulphuration can be carried out oxidatively with metal salts (British Pat. No. 793,802, Dutch Pat. No. 81,326), e.g. with lead, copper, zinc or iron-HI salts, iodine, alkali metal hypochlorites and -chlorites, preferably with those of potas sium and sodium (French Pat. No. 1,311,855), also with suitable acid halides such as phosgene and phosphorus oxychloride (D. Martin et. al., Chem. Ber., 98, 2425-2426 (1965)), as well as with elementary chlorine and ammonium sulphide (DAS 1,192,139) or chloramine T (British Pat. No. 1,024,913).

Isothiocyanobenzazoles of formula I can be prepared, for example, by the reaction of aminobenzazoles, which can be obtained from nitrobenzazoles in the usual manner by reduction with zinc, iron or SnCl in acid solution, with catalytically activated hydrogen, or with sodium borohydride, with thiophosgene in mineral acids, preferably concentrated hydrochloric acid, according to:

III

The reaction with CSCl can however also be smoothly performed in the presence of an acid-binding agent such as an organic base, e.g. triethylamine, pyridine, N,N-dimethylaniline, or of an inorganic weak base such as CaCO BaCO Na-acetate, NaHCO KH PO This variant will be advantageously used in the case of the hydrolysis-sensitive conversion of an aminobenzoxazole into isothiocyanobenzoxazole, in order to avoid the benzoxazolering-opening according to Ia II, which would have to be subsequently re-closed, if at all possible, by heating in a further stage of the process.

On the other hand, this reaction behaviour can for a number of isothiocyanobenzoxazoles be made the basis of a further production process. Those compounds of formula Ia wherein n=0 can be obtained from the basic aminoacylaminophenols of formula IV (with R =H or -COR by reaction with thiophosgene (or with one 10 of the other reagents given under the methods (a) to (h), and subsequent ring condensation according to:

Salts of isothiocyanobenzoxazoles Ia can be produced, on account of hydrolysis sensitivity, practically only with weak acids, preferably organic acids. On the other hand, salts of benzothiazoles, Ib, or of benzimidazoles Ic, can be prepared with either strong or weak acids. The hydrochlorides of these two last-mentioned subgroups can also be obtained direct from amino compounds of formula IIIb or IIIc if thiophosgene is used for the reaction in anhydrous solvents, or in mineral acids such as hydrochloric acid or sulphuric acid.

Aminobenzoxazoles of formula 111a and their immediate precursors, the nitrobenzoxazoles, are in some cases known, or can be produced by known methods [cp. M. A. Phillips, J. Chem. Soc., 1928, 122; ibid, 1930, 2685-2730; I. K. Ushenko, Zh. Obsc. Ch., 30, 2658-69 (1960); A. Cerniani and R. P'asserini, Ann. Chim. (Roma), 44, 3-10 1954)].

The ring closure of a N-acylated or N,O-bisacylated o-aminophenol to the corresponding benzoxazole by simple distillation with the splitting off of water, as corresponds also to the reaction behaviour of the compound II or V With conversion into Ia, is described by F. M. Harner, J. Chem. Soc., 1956, 1480. The reaction can be advantageously performed also with condensation agents such as ZnCl POCl P 0 or H BO [cp. M. A. Phillips, J. Chem. Soc., 1928, 121; US. Pat. 3,158,610]. The use of H BO is particularly favourable and reduces the risk of the formation of resinification products.

Aminobenzothiazoles of formula IIIb and their precursors, the nitrobenzothiazoles, are in some cases likewise known, or can be produced by known methods (cp. Beilsteins Handbuch der Organischen Chemie [Handbook of Organic Chemistry], 27, p. 47; ibid., 27, II, 427; Chemical Abstracts, 48, 2689d; ibid., 49, 6232b; ibid., 49, 11625b; ibid., 57, 13925a; ibid., 69, 10032; ibid., 70, 57724; I. K. Ushenko, Zh. Obsc. Ch., 30, 2658-69 [1960]; British Pat. No. 913,910 [1962]; French Pat. No. 1,379,470 (1964); British Pat. No. 598,985 (1948); T. Takahashi and J. Okada, J. Pharm. Soc. Japan, 75, 277-280 [1953]).

Aminobenzimidazoles of formula IIIc as well as their precursors, nitrobenzimidazoles, are in some cases knoWn, or can be produced by known methods (0. Kym, J. Prakt. Ch., 75, 323 [1907]; A. Ricci, Gazz. Chim. ItaL, 97, 741-749, 758-768 [1967]; Shotaro Nakajima et al., Yakugaku Zasshi, 78, 1378-1382 [1958]).

A general method for the production of most of the starting compounds III comprises the conversion of 2- thiolbenzazoles by chlorination into 2-chlorobenzazoles, and the introduction of the groups --OR, or N(R (R.,) with the aid of a corresponding alcoholate or see. amine; or, for the introduction of the group -18R the reaction of the basic 2-thiolbenzazole direct with a healide Hal-R The substituents O N and R can be thereby introduced at a point of time appearing suitable, before or after this production process. An oxidation, performed before introduction of the isothiocyano group, with, e.g. NaOH/H O converts the group -S--R into SO -R or SO -R In the case n= of the direct bond of R to the heterocyclic ring, it is preferable to commence with a corresponding ortho-substituted aniline (as has already been indicated with respect to the production of benzooxazoles in the conversion IV- Ia), in that a corresponding 0- aminothiophenol undergoes the ring closure reaction with, e.g. an acid halide HalCO-R or an acid anhydride O(COR to give benzothiazole; or in that a corresponding o-phenylenediamine bis-acylated by COR is condensed to benzimidazole; or in that, e.g. an o-phenylenediamine substituted by R is reacted with urea to give 2- hydroxybenzimidazole, which can be chlorinated with POCI in the 2-position, and thereupon nitrated in the condensed benzene ring.

EXAMPLE 1 Production of 2-[n-amyl]-6-isothiocyano benzoxazole (Compound No. 1.9)

(a) An amount of 188 g. of crude 5-nitr0-2-caproylaminophenol is heated with 46 g. of boric acid with elimination of water, until the internal temperature has attained 210220 C. The mixture is then cooled, stirred with chloroform and filtered. The filtrate is repeatedly Washed with water, dried, and the solvent removed. The 2-[n-amyl]-6-nitro-benzoxazole remaining boils at 128- 132 C. (0.1 torr.).

(b) An amount of 122 g. of 2-[n-amyl1-6-nitro-benzoxazole is dissolved in 1500 ml. of distilled anhydrous ethanol, and, after the addition of g. of Raney nickel at room temperature to slightly elevated temperature (below 35 C.), hydrogenated. Raney nickel is filtered off under suction, the filtrate separated from the ethanol, and the residue remaining recrystallised from cyclohexane to obtain Z-[n-arnyl]-6-amino-benzoxazole, M.P. 5759 C.

(0) An amount of 40.8 g. of 2-[n-amyl1-6-amino-benzoxazole is dissolved in 370 ml. of anhydrous acetone. After the addition of 50 g. of powdered anhydrous CaCO the mixture is cooled to 0 C., and at this temperature an addition made dropwise with stirring of a solution of 29.7 g. of CSC1 in 30 ml. of anhydrous acetone. The mixture is then stirred at 0 to 5 C. for five hours and filtered. After concentration of the filtrate at 30 C. in a slight vacuum, the residue is recrystallised from petroleum ether to obtain 2-[n-amyl]-6-isothiocyano-benzoxazole, M.P. 31-34 C.

12 EXAMPLE 2 Production of 2-[n-amyl]-6-isothiocyano-benzoxazole (Compound No. 1.9)

(a) An amount of 22 g. of 2-caproylamido-5-nitrophenol is dissolved under nitrogen in 500 ml. of distilled dioxane, and, after the addition of 8 g. of Raney nickel, hydrogenated at room temperature or at 3040 C. until the reaction is complete. Raney nickel is filtered off under suction. The obtained filtrate with the contained Z-caproylamid0-5-amin0phen0l can be used direct for the subsequent thiophosgenation. It is also possible to firstly isolate the intermediate by removal of the dioxane by distillation.

(b) An amount of ml. of cone. hydrochloric acid is added at 0 to 5 C., with stirring, to a solution of 18 g. of 2-caproylamido-S-aminophenol in 300 ml. of water. There is then added dropwise to this mixture, in the course of 20 minutes, 14 g. of CSCI the Whole is subsequently stirred for 12 hours at 5 C., and the final product dried; it melts, after recrystallisation from benzene, at 148-150 (0) The obtained 2-caproylamido-5-isothiocyanophenol can be cyclised in an N -stream by rapid heating at ca. 210 C., in the presence of boric acid, for 15 minutes with elimination of Water to give 2-[n-amyl]-6-isothiocyanobenzoxazole, which can be obtained by the addition of petroleum ether and subsequent cooling.

EXAMPLE 3 Production of Z-methyl 6 isothiocyano-benzoxazole (Compound No. 1.2)

An amount of 10.4 g. of 2-acetamido-5-isothiocyanophenol which was obtained by thiophosgenation from 2- acetamido-S-aminophenol, is heated with 3.4 g. of boric acid for 15 minutes at 200 C., and then immediately cooled. The residue is extracted with hot cyclohexane; the solution is concentrated by evaporation, cooled and petroleum ether added, whereby the desired final product crystallises out, M.P. 6870 C.

It is possible to produce in an identical manner to that described in Examples 1 to 3, or by a corresponding method previously described, the following isothiocyanobenzoxazoles of formula Ia, from which corresponding acid addition salts are obtainable:

SON (Y)n-Rl N (Ia) Compound number SON- position R2 R1 Physical data 6 H H 6 H CH: M.P. 6870 C. 6 H CzHs M.P. 64-68 C. 6 H 11-05111 6 H iso-caHy 6 H 71-04 9 6 H lS0-C4Ha 6 H tern-0 H; M.P. 7779 C. 6 H n-CsHn M.P. iii-34 C. 6 H n-Octyl M.P. id-42 C. 6 H B-heptadecenyl 1113 15498 6 H =C a 6 H Cyclopropyl 6 H 2,3-dimethyleyclopropyl 4 H CH: 7 H CH3 5 H CH3 M P. Sit-84 C 5 II CzHs M P. 43-48" C 5 II 1L-Ca 7 5 H 1so C3H1 5 H 7Z-C4 9 5 H iso-CiH M.P. 49-51 C. 4 H !L 05H 7 H 71 C5111 5 H tern-04H 5 H 'n-CsHn 5 H Heptadecyl M.P. 70 C.

S SON CHOH (Compound No. 2.8) N

M.P. 52-54 C.

EXAMPLE 5 Production of 2-ethy1-6-isothiocyano-benzothiazole (Compound No. 2.6)

(a) An amount of g. of thiophosgene (dissolved in 10 ml. of acetone) is added dropwise in the course of minutes at 5-10 C., with stirring, to a solution of 17.8 g. of Z-ethyl-6-amino-benzothiazole, 150 ml. of acetone, 8.4 ml. of cone. hydrochloric acid and ml. of Water. 20 After four hours stirring, the solution is allowed to stand for ten hours at room temperature; it is then filtered and concentrated in vacuo (water-jet vacuum). The residue recrystallised from dioxane is 2-ethyl-6-is0thiocyano-benzothiazole-hydrochloride, M.P. 116- 120 C.

From the dioxane filtrate, the residue obtained by concentration by evaporation is recrystallised from cyclohexane, and the free base 2-ethyl-6-is0thi0cyan0-benzothiazole, M.P. 69-73 C., is obtained, from which, by dissolving in anhydrous dioxane and introduction of HClgas at 10, likewise the hydrochloride is formed, which is obtained as precipitate, M. P. 116-120 C.

(b) An amount of 13 g. of 2-ethyl-6-isothiocyanobenzothiazole-hydrochloride is stirred with ml. of chloroform and 100 ml. of saturated sodium carbonate solution for 15 minutes at 10 C. The chloroform is then separated, washed with water, dried with Mg-sulphate, and concentrated by evaporation. There is obtained, after recrystallisation of the residue from ligroin/ petroleum ether, as pure final product the compound of the formula S soN CzHl N (Compound No. 2.6)

It is possible to obtain in the same manner as that described in Examples 4 and 5, or by one of the methods previously indicated, the following isothiocyanobenzothiazoles of formula Ib S SON I )n l (n= 0) N from which corresponding acid addition salts are obtainable:

Compound SON- number position R2 R1 Physical data 2.1 4 H H M.P.120-12Z C. 22 4 H CzHa 2 7 H 02115 2.4 6 H H M.P.125" C. 2.5 6 H CH3 M.P.118- C. 2.6 6 E 02115 M.P.6973 C. 2.7 6 H 'n-CaH1 M.P.60-62C 2.8 6 H iSO-CaH1 M.P.5254C 2.9- 6 H sec-C4139 B.P.0-oa142 C. 2.10 6 H tert.-C4Ho M.P.87-90 C. 2.11 6 H 'IZ-C5Hl1 M.P.7577 C. 2.12-. 6 H iso-C5Hn 2.13 6 H n -CsH11 2.14 6 H -n-C11H23 M.P.51-53 C.

2.15 6 H CHC4Hm 2.16 6 H -C=CH3 2.17 6 H CHz-CH=GHCH; 2.18 6 H Cyclopropyl 2.19 6 H Cyclopentyl 2.20 6 H Cyclohexyl 2.21 5 H Isopropyl M.P.34-36" C. 2.22 6 4-01 CH: 2.22- 6 7-Cl CH 2.23 6 5-011: CH: 2.24 6 5-CH30- CH3 2.25 5 6-C2H5 Ha 2.26 5 4 2H5 -n-C5H11 2.27--- 5 G-CHsO n-C5Hn 1 Bieyelo-[2,2,11-hept-5-en-2-ylmethoxy.

1 7 as well as following compounds of formula Ib with n Physical data Compound SON- n her position R:

see. C4H see. 0411a oooss loossoo HHHHHHHHHHHHHHH 4" u iadrialii M.P. 66-68" C.

M.P. 170 C.

0H; M.P. 252-256 0.

EXAMPLE 6 Production of 5(6)-isothiocyano-2-methyl- 30.8 g. of 5(6)-amino-2-n-propylthio-benzimidazole with 300 ml. of acetone and p 32.5 g. of calcium carbonate,

benzirnidazole (Compound No. 3.2)

and the whole subsequently stirred at 0 C. for 4 hours. The precipitate is filtered off under suction, stirred with dilute acetic acid, extracted with ethyl acetate, and treated with active charcoal; it is afterwards filtered 01$ from the charcoal, diluted with petroleum ether, and again filtered 0E. The solution is distilled off to dryness, the residue dissolved in hot acetouitrile and diluted with water. There is obtained, after cooling and filtration under suction, the compound 2-n-propylthi0-5(6)-is0thi0cyan0- benzimidazole, M.P. 142-145 C.

s OM R wan u Sh f. m o t ht ePa m e GGQP .m mmkmo r rmd a m m m sm m h mSd m e 6 m o s mfam fl, m 6 mm m mnm ea b m m 4 mmu i 00 d 4 {W H C 550 mm .m fa I .0 .wC m N dh a n 6 W n a O .1 o1 N -30ft. .1 16 f d wm m M W e ow m e 06f. 426t t al. ifii i g rhours stirring at C the suspension is It is possible to obtam, in the same manner as described filtered under suction, and subsequently washed with i t examples, or PY 9 9 the et odspreviously chloroform and a little water The moist suctiomfilter indicated, the following lsothiocyano-benzrmidazoles of residue, dissolved cold in 800 ml. of alcohol, in filtered formula through Hyfiosupercel, cooled to 0 C., and afterwards precipitated with 1000 m1. of water. The precipitate is filtered off with suction, and dried at 45 C./l2 torr. There is thus obtained 5 (6 )-is0thi0cy2ma-2-methyl-benzimidazole, M.P. 217-219 C.

(for V 0, R =H; then the 5- and 6-position as well as the (n= 4- and 7-position are identical, provided also R TABLE-Continued Compound SCN- number position Ra Y R1 Physical data 3.69 6 Beuyzl 3.70 5 Acetyl O 3.71-: 6 -n-C H as well as the compounds thiocyano-benzimidazole, M.P. 118-122 C.,

3.80 2-isopropylthio-5 6) -isothiocyano-benzimidazole M.P. 159-162 C.,

3.8 1 1-ethoxycarbonyl-2-n-butylthio-5 (6) -isothio cyanobenzimidazole, M.P. 5962 C.,

3.82 1-n-butoxycarbonyl-Z-methylthio-5 6 -isothiocyano-benzimidazole, M.P. 77-80 C.,

3 .83 l-propionyl-2-isopropylthio-5 (6 -isothiocyanobenzimidazole, M.P. 7376 C.

Tests on mice infested by Hymenolepsis nana The active substances in the form of a suspension were administered by stomach probe to white mice infested with Hymenolepsis nana. Five animals per test were used. The active substances were administered to each animal once daily during three successive days. On the eighth day after commencement of the treatment, the animals were killed and dissected.

After dissection of the test animals, an evaluation was made on the basis of a count of the tapeworms present in the intestines. As a control, an examination was also carried out on untreated mice which had been simultaneously and identically infested.

The agents were tolerated asymtomatically by the mice.

Infestation oi the 5 test Infestation of the animals on control animals Active substance dissection on dissection 2-methy1-6-isothlocyano-benzoxazole (dose: 100 mg. AS/kg. of body weight 0000 124-57 2-ethyl-5-isothlocyano-benzoxazole (250 mg. AS/kg.) 26-713-1936 2-methyl-6-isothiocyano-benzothiazole (750 mg. AS/kg.) 1112-1216-16 2-ethyl-6-isothiocyano-benzothiazole (750 mg. AS/kg.) 0-0-0-0-0 1112-121616 2-isopropyl-fi-isothiocyano-benzothiazole (750mg. A kg.) 00000 89910-11 4isothiocyano-benzothiazole (750 A kg. 0000-0 8991011 -isothiocyano-2-n-octyl-benzoxazole (750 mgJkg.) 0000-0 11-16202947 6-lsothiocyano-2-mercapto-benzoxazole (750 mg./kg.) 00-0-00 0-1-2-2-4 5-lsothiocyano-2-meth lthio-benzv oxazole (750 mg./kg. 000-00 g 6-7-9-10-12 2- n-butoxy4i-isothiocyano-benzothlazole (300 mgJkg.) 00000 0-1-2-4-5 24tbutylthio-6-isothioeyano-benzotln'azole (750 mg./kg.) 0-0-0-0-0 23-101113 6-isothiocyano-2-methy1su1fonyl benzothiazole (750 mgJkg.) 0-0-0-0-0 2-31011--l3 6(5)-isothlocyano-Z-n-propylthiobenzimidazole (750 mgJkg.) 0-000-1 6-14151825 2-ethoxy-6-isothioeyano-benzoxazole (500 mgJkg.) 0-0-0-0-0 0-3-11-12-14 Tests on mice infested by mouse threadworms (Oxyuris) The active substance was administered in the form of a suspension by means of a stomach probe to white mice infested with mouse threadworms. Five animals were used for each test. The active substances were administered to each animal once daily during three successive days. The animals were then killed on the eighth day after coinmencement of the treatment and dissected.

After dissection of the test animals, an evaluation was made on the basis of the count of mouse threadworms present in the intestines. Untreated mice which had been simultaneously infested served as a control The agents were tolerated asymtomatically by the mice.

Infestation of the test Infestation of animals on control animals Active substance dissection on dissection 2-ethyl-5-isothioeyano-benzoxazole 88--1415-20 5-isothiocyano-2-methy1thiobenzoxazole (750 mg./kg.) 0-0-0-0-0 201012-1824 24t-butoxy-6-isothiocyanobenzothiazole (300 mgJkg.) 00-000 1-2-3-3-4 fi-isothiocyano-21nethylthio- 1 benzothiazole (500 mgJkg.) 0-0-0-0-0 1--2-3-34 Z-ethylthio-fi-isothioeyanobenzothiazole (500 mg./kg.) 00000 l-methoxycarbonyl-2-n-propyI-5- chloro6isothiocyano-benzimidazole (75o mgJkg.) o-o-o-o-o 7-8-18-26-40 Tests on mice infested by Nematospz'roides dub ius A The active substances in the form of a suspension were administered by a stomach probe to White mice which had been infested with Nematospiroides dubius. Five animals per test were used. The active substances were administered to each animal once daily on three successive days. On the eighth day after commencement of the treatment, the animals were killed and dissected.

After dissection of the test animals, an evaluation was made on the basis of the count of worms present in the intestines. Untreated mice which had been simultaneously and identically infested served as a control.

The agents were tolerated asymtomatically by the mice.

Infestation The control test for lever fiukes after dissection was ofthefitest Infestation of negative in all cases.

animals on animals on Active substance dissection dissection 2-ethyl-5-isothioeyano-benzoxazole Determination of the ant (250 mg of active Substance per kg 5 helmmt ic action on fowl infested or body weight) 0 0 o 1 22 1 o Wlth A-Warldla gall! 2-11-amyI-6-isothiocyano-benzoxazole s 1 s (fi i1i i""ti '1'E""'1ii"'1" 79 11 M 20 cyauome yenzo azoe (750 mg./kg.) o 0 0 o 0 12 12 1g 23 25 1 f chlckFns were Infested eggs of 2-isopropy l-6-isothi0cyano- Ascarzdza gallz (ascarides). A group of chickens was benzotlnazole (750 mgJkg.) 0-0-0-0-0 4-9-11 54som1ocyanwzmctybbenzomole used for each test. 4-5 weeks after infestation, the active (750 mgJkg.) 0-0-0-0-3 49111417 5480thiocyanwmethyhbemoxaZ016 substances were administered to the chickens in the 2 t2go mg/ikgiki 5 l 7 3. g. 10 form of one daily dose on three successlve days. Infested oxazole (750 mg.[kg.) 0-0-0-0-0 13-14-1s-20 24 r 0 Sea I la ga ll excreted by f test 5-lsolihltljcygagfl-mit ylthiobenzgroup in the course of 5 days after the first administraon o e 0 0 0-0 0 eisoti iiocsiano et iiiixy-benzo- 7 7 9 tlon was determmed daily, and the number of worms still thiazole (750 mg./kg.) 000-00 19-21-22-27 6 isothiocyano z methylthiobenw present in the intestines following dissection on the 5th thiazole (500 mg./kg.).- 1; 0-0-0-0-0 1s-1s-21-22-27 day of the test likewise counted. The number of chickens enzo free from Worms was also determined.

Daily Number ofAscaridia galli dose, from 5 chickens mg./kg. of body Found after Active substance weight Excreted dissection 2-methyl-G-isothiocyanobenzothiazole 750 49 00000 2-ethyl-6-isothiocyanobenzothiazole 750 41 00010 2-ethyl-6-isothioeyanobenzothiazolc-hydrochloride. 750 79 000-00 Z-(n-amyl)-6-isothiocyanobenzothiazole 750 66 0000O 2-isopropyl-G-isothiocyanobenzothiazole- 750 63 000O0 2-methyl-6-isothiocyano-benzoxazole. 500 26 0-O00-10 2-(n-amyl)-6-isothiocyanobenzoxazole 750 119 2-n-octyl-6-isotl1iocyano-benzoxazole. 750 116 0 0-O00 2-ethoxy-6-isothiocyano-benzoxazole.. 750 103 7 2-cyclohexy1thio-6-isothiocyano-benzo 750 84 000-14 fi-isothiocyano-Z-methoxy-benzthiazole. 750 143 0-0-0-1-3 fi-isothiocyano-2-methy1thio-benzothiazol 500 131 0-0-0-0-0 fi-isothiocyano-2-ethylthiobenzothiazole 500 181 000-00 6-isothiocyano-2-n-butylthio-benzothiazole 750 145 0-0-041-0 6(5) ehloro 5(6)-isothiocyano-2m-propyl-benzimidnmle 750 65 OO0O-5 Tests on rats infested by Fasciola hepatica White laboratory-rats were infested with common liver fiukes (Fasciola hepatica). After expiration of the prepatient period, the infestation of the rats by common liver flukes was determined by means of three independent excrement analyses.

In each test, two infested rats were treated in each case with the active substance, administered in the form of a suspension by stomach probe, once daily on three successive days. An excrement analysis to determine the content of common liver fluke eggs was made once weekly in the third, fourth and fifth week after administration of the active substance. At the end of the fifth week after commencement of the test, the test animals were killed and examined to determine whether liver flukes were still present.

Dally Excrement examination ACTION AGAINST PATHOGENIC BACTERIA AND FUNGI Determination of the Minimum Inhibition Concentration (MIC) Samples of a dilution series (commencing at 100 p.p.m.) of active substance dissolved in methyl Cellosolve are intimately mixed at ca. 50 C. with liquid agar. The warm mixture is poured into glass dishes of 10 cm. diameter to form a 0.5 cm. deep layer, and then allowed to cool. The cultures of bacteria and of fungi are then applied in the form of point by means of an automatic dosing device, the concentration being from 10 to 10 germs per ml. The dishes are kept in an incubator at 37 C.

The following gram-positive strains of bacteria were examined:

3 2 72, r eggs (3X) Staphylococcus aureus K 465 oi Befglre Aitgr Staphylococcus aureus K 444 O y me C8- me 108- Aetive substance weight tion tion 22; 22:22: 5 2-methyl-fi-isothloeyano-benzoxazole.. 100 Positive. Ne ative. 2-ethy1-5-isothiocynno-benzoxazolo-. Do. Streptococcus agalactiae 100 2-(n-amyl)-6-isothiocyano-benzoxazole. Do. rep coccus agalactlae M 101 '%L Erysipelothrix rhusiopathiae K 593 2-ethyI-Msothiocyano-benzothiazole Do. Listeriae monocytogenes Type IV-b 2-isflprorliyl-fi-isothiocyano-benzo- Do.

t azo e. 1 tin o-2-n-oct l-benzoxazole... D gj zg gggg g 3 The following gram-negative strains of bacteria were zole. examined:

2-1sopropylthio-5-isothiocyano- 100 do... Do.

benzoxazole. 5-isolthiocyano-2-methylthio-benzoxa- 100 .-.do Do. Escherichia coli G 70/1172 Z0 8. 2-1slepropoxy-e-lsothlecyano-benzm 50 ....do Do. 5 2 2 5 139382-13 sc eric ia c0z'7 :B

hi0 no-2-meth lthio-benzo- 200 do 58: y Do Escherzchza col: M g 200 Escherichia coli 7: 1.7,8

am e.

Salmonella gallinarum VBIB 25 Salmonella cholerae suis VBIB Salmonella pu'llorum typhimurium VBIB Salmonella multocida K 753 Brucella suis VBIB Proteus rettgeri l07-1531 Klebsiella pneumoniae 107-153-3 The following strains of fungi were examined:

Aspergillus niger K 617 Candida pseudotropicalis CDC 48 Candida krusei CDC 46 Candida krusei M 500 Pseudomonas sp.

Trichophyton gallinae K 454 T richophyton verrucosum K 424 T richophyton quinckeanum K 883 Hefe M 500 Hefe M 501 An evaluation was made after 24 hours. Values of minimum inhibition concentration were obtained for compounds of formula I which were clearly below the starting concentration of 100 ppm.

The following examples describe the production of preparations of anthelmintically effective agents and feed additives. The term parts denotes parts by weight.

DISPERSIBLE POWDER The following constituents are used in the preparation of 50% dispersible powders:

The given active substances are mixed with the carriers and distributing agents and then finely ground. The obtained powder can be mixed with liquid or pasty feeding stuffs and thus administered to domestic and'useful animals.

PASTE The following substances are used in the preparation of a 40% paste:

40 parts of active substance according to the invention, 2.5 parts of sodium lignin sulphonate, 0.3 part of sodium benzoate,

10 parts of glycerin,

"47.2 parts of distilled water.

The active substance and the distributing agents are intimately mixed. The thus obtained paste is mixed with liquid and pasty feeding stuffs for administration to domestic and useful animals.

FEED ADDITTVE PRESS CAKES The following substances are used in the preparation of 35% feed additive press cakes:

35 parts of active substance according to the invention, parts of molasses,

5 parts of licorice powder,

25 parts of dried green meal,

parts of ground bran.

The active substance and the distributing agents are mixed and formed into press cakes in an animal-feed press. The obtained feed additive concentrate is mixed with the feeding stuffs and thus administered to domestic and useful animals.

EMUIJSI-FIABL'E CONOENTRATE An emulsifiable concentrate is obtained by the mixing together of the following constituents:

2 parts of active substance according to the invention,

2 parts of a polyethyleneoxypropylene glycol having .a molecular weight of ca. 3000 (Pluronic L 64), and

96 parts of acetone.

The obtained concentrate can be diluted with water to give emulsions of any desired concentration, and thus administered, e.g. as drink to domestic and productive animals.

OILY FORMULATION 40 parts of active substance according to the invention are ground as finely as possible in a suitable mill, and subsequently homogeneously mixed, e.g. on a roll mill, with 60 parts of arachis oil (peanut oil).

These oil-pastes can be administered orally to the animals.

What is claimed is:

1. A compound of the general formula wherein the SCN group is in the 4-, 5-, 6- or 7-position,

R represents hydrogen, a straight-chain or branched alkyl or alkenyl radical having at most 17 carbon atoms, an alkyl or alkenyl radical having a total of at most 6 carbon atoms and substituted by halogen, CN, OH, C -C alkoxy, C -C alkylthio or di- (C C )alkylamino, an optionally C -C alkyl-substituted mono-, bior tricyclic cycloalkyl or cycloalkenyl radical having 3 to 10 carbon atoms in the ring structure, which can "also be bound by way of a CH;, group to the substituent Y or to the 2-position of the heterocycle,

R represents hydrogen, halogen or an alkyl or al-koxy.

radical having at most 4 carbon atoms,

X represents oxygen, sulphur or R represents hydrogen, an alkyl or alkenyl radical having at most .5 carbon atoms, a phenyl or benzyl radical, a dimethylaminoor diethylamino-alkyl radical having 2-5 carbon atoms in the alkyl chain, an alkoxycarbonyl radical having 2-5 carbon atoms, acetyl, propionyl, trichloroacetyl, benzoyl, or a C -C saccharide group,

Y represents oxygen, sulphur, -SO'--, SO or n is the number 0 or 1,

R represents hydrogen, an alkyl or alkenyl radical having at most 5 carbon atoms, or together with the N- atom and the substituent R a saturated or unsaturated heterocycle having 4 to 6 carbon atoms which may also contain a further hetero atom O or S selected from the group consisting of pyrrolidine, piperidine, Z-methylpiperidine, 4-methylpiperidine, piperazine, N'-methyl, =N,N'-di-methyl and N-ethylpiperazine, morpholine, isomorpholine, thiomorpholine and hexamethyleneimine, or the group b and R stands for hydrogen, methyl or ethyl,

27 and their acid addition salts non-toxic for warm-blooded animals.

2. Compounds and their salts according to Claim 1 which correspond to the formula wherein the SCN group is in the 5- or 6-position, and the substituents R R X, Y and n have the meanings defined in Claim 1.

3. Compounds and their salts according to Claim 2 which correspond to the formula wherein the substituents R and R have the meanings defined in Claim 1.

4. Compounds and their salts according to Claim 2 which correspond to the formula wherein the substituents R and R have the meanings defined in Claim 1.

5. Compounds and their salts according to Claim 2 which correspond to the formula wherein the substituents R and R have the meanings defined in Claim 1.

6. Compounds and their salts according to Claim 2 which correspond to the formula wherein the substituents R R and R have the meanings defined in Claim 1.

7. Compounds and their salts according to Claim 2 which correspond to the formula R2 0 s ON I R1 wherein the substituents R and R have the meanings defined in Claim 1.

8. Compounds and their salts according to Claim 2 which correspond to the formula wherein the substituents R and R have the meanings defined in Claim 1.

9. Compounds and their salts according to Claim 2 which correspond to the formula wherein the substituents R and R have the meanings defined in Claim 1.

10. Compounds and their salts according to Claim 2 which correspond to the formula wherein the substituents R and R have the meanings defined in Claim 1.

wherein the substituents R R and R have the meanings defined in Claim 1.

12. Compounds and their salts according to Claim 2 which correspond to the formula R2 IL s CN 111 wherein the substituents R R and R have the meanings defined in Claim 1.

References Cited UNITED STATES PATENTS 2,932,649 4/1960 Metivier 260-307 D 3,720,686 3/1973 Narayanan et al. 260309.2 3,586,670 6/1971 Brenneisen et al. 260307 D OTHER REFERENCES Bloom et al.: Defensive Publication 701,845, 857 0G 696.

RICHARD GALLAGHER, Primary Examiner US. Cl. X.R.

260-209, 243 B, 244 R, 247.1, 247.2 A, 247.5 B, 268 BC, 293.57, 293.58, 293.61, 304, 305, 306, 307 D, 309.2, 454; 424180, 246, 248; 250--267, 270, 272, 273, 302 

1. A COMPOUND OF THE GENERAL FORMULA 